PROTAC And Other Protein Degradation Technology

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PROTAC And Other Protein Degradation
Technology

PROTACs, full name is Proteolysis-Targeting Chimeras. This technology is a new
drug development direction that has emerged in recent years. To put it simply, PROTAC
is a heterozygous bi-functional small molecule compound containing two different ligands:
one is the ligand of E3 ubiquitin ligase and the other is the ligand that binds to the target
protein in the cell. The two ligands are connected by linker to form a "trisome" polymer-the
target protein ligand-Linker-E3 ligand.

The development history of PROTAC

In 2001, the team of Professor Craig M. Crews of Yale University and Professor Raymond
J. Deshaies of California Institute of Technology first proposed the concept
of PROTAC and reported the first PROTAC molecule-Protac-1 after a series of proof of
concept.

The structure of Protac-1

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In 2004, the polypeptide PROTAC based on Von Hippel Lindau (VHL) E3 ubiquitin ligase
was reported for the first time.

In 2008, the team of Professor Craig M. Crews of Yale University synthesized the small
molecule PROTAC containing nutlins for the first time and successfully recruited AR onto
mouse double minute 2 (MDM2). And acts as an E3 ubiquitin ligase to trigger its
ubiquitination and proteasome degradation.

In 2010, the first cIAP-based small molecule PROTAC was reported.

In 2013, Crews founded the first pharmaceutical company focused on PROTAC.

In 2015, PROTAC with nanomolar degradation activity based on VHL and CRBN was
discovered.

In March 2019, Arvinas announced that its first AR degradant ARV-110 for the treatment
of prostate cancer entered phase I clinical trials (NCT03888612). ARV-110 is the first
PROTAC molecule publicly reported to enter Phase I clinical trials, marking a new stage in
the research of PROTAC technology.

The structure of ARV-110

On October 23, 2019, Arvinas announced the initial results of phase I clinical trials of
ARV-110 and ARV-471: Oral PROTAC is safe and tolerated in cancer patients.

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The structure of ARV-471

The advantages of PROTAC

As Arivinas announced the positive initial phase 1 clinical results of two oral PROTAC
molecules, ARV-110 (AR) and ARV-471 (ER), the prospects for PROTAC are very good.
Compared with small molecule inhibitors, it shows great potential in the following aspects.

PROTAC is expected to slow down the occurrence of resistance to small molecule
inhibitors. PROATC can quickly bind to the target protein and induce its degradation at a
lower concentration, which is of positive significance for overcoming the drug resistance
caused by the target protein itself.

PROATC is expected to degrade the target protein that was not druggable, and then
develop corresponding drugs. For example, signal transducer and activator of
transcription 3 (STAT3) is a key factor in cell survival, proliferation, angiogenesis,
metastasis and chemotherapy resistance. However, there is no obvious direct action
pocket in the structure of STAT3, which directly blocks the development of STAT3
inhibitors, and no effective drugs have appeared yet. However, professor Wang
Shaomeng’s team has developed a STAT3 degrading agent, and it has shown good
effects both in vivo and in vitro.

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PROTAC can affect protease activity and non-enzymatic activity by degrading the
entire kinase. For example, focal adhesion kinase (FAK) provides a scaffold for a variety
of signal proteins and plays a vital role in the process of tumor invasion and metastasis.

The challenges of PROTAC technology

What appears to be a straightforward mechanism of action is not so simple in practice.
Like all emerging technologies, PROTAC technology also has some challenges. This
article "The PROTAC gold rush" published on Nature-Biotechnology pointed out that
being able to "pull" E3 ligase to the vicinity of the target protein does not guarantee that
the latter can be degraded. In practice, a stable ternary structure needs to be formed
between the different molecules and ubiquitin can be carried out smoothly. In addition,
even if proteins are successfully ubiquitinated, it does not mean that they will be degraded
smoothly.

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The mechanism of PROTAC Technology (Image source: Reference [1])

Another challenge in the development of PROTAC molecules is to ensure the orally
bioavailable of this class of drugs. Professor Wang Shaomeng, a protein degradation
expert at the University of Michigan in the United States, pointed out in the article that the
molecular weight of PROTAC molecules is about 0.7 to 1.1 kDa, which has a larger
surface polar area than traditional small molecules. These will affect the penetration
of molecules. And compared with mouse models, the oral bioavailability of these
molecules in humans is lower. The mouse model cannot be used to predict the results in
humans, which further increases the complexity of new drug discovery.

In addition, it is also pointed out in the article that a bottleneck in the development of
PROTAC molecules is the selection of E3 ligase. In humans, there are about 600
different E3 ligases. But most companies that are developing oral protein degrading agent
focus on the Cereblon-based E3 ligase system. On the one hand, this is because the
relevant research has been relatively proficient, and the related molecules are smaller,
more flexible, and more medicable; on the other hand, it is also because some of the other
options are collectively more complex and prone to unintended consequences. This is
certainly a viable pioneering strategy at the moment. But in the long term, we need to
find targets beyond Cereblon -- in certain tissues, other E3 ligases may be more
active.

The article also mentioned some other challenges of PROTAC technology. For
example, the types of proteins that can be degraded are relatively limited. For
membrane proteins that are less exposed to the cytoplasm, it may be difficult to find
binding sites, and it is also difficult to add the ubiquitin label. In addition, if a protein has
many repetitive sequences or polymerizes, it will also make drug design difficult. Of
course, like other drug molecules, new drug developers also need to limit its potential
toxicity and off-target effects.

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PROTAC and other protein degradation

technology

Of course, drug developers are well aware of these challenges and are trying to find
solutions. If these bottlenecks can be overcome, PROTAC will undoubtedly unleash
greater potential. Compared with traditional protein inhibitors, the protein degradation
technology represented by PROTAC does not just inactivate the target protein. In many
cases, proteins act as structural scaffolds in addition to their own biochemical
functions. In this regard, protein degradation therapy has a unique advantage. And
theoretically, molecules such as PROTAC can detach from the target protein after it has
been degraded, binding to more targets. As a result, the doses used are expected to be
lower. Of course, this advantage of the PROTAC molecule has not been fully
demonstrated in some clinical trials so far, but it is expected to become a reality in the
future.

We also need to understand that PROTAC is not the only technology for protein
degradation. As mentioned in that article, many companies are currently
developing a type of protein degradation technology called "molecular glue".
Unlike PROTAC molecules, molecular glue only binds E3 ligase to change the
shape of its surface, thereby recruiting target proteins and completing protein
degradation. Lenalidomide developed by Celgene can be regarded as the prototype of
molecular glue, which can activate cereblon protein, degrade Ikaros and Aiolos
transcription factors, and treat multiple myeloma.

Unlike traditional new drug development, the development of molecular glues is a bit
upstream-it is difficult to select a disease-related target first, and then proceed with drug
development. On the contrary, it often screens molecules that can bind to E3 ligase until it
obtains the desired properties, and then uses it for large-scale screening of protein
databases to find protein targets that can be degraded.

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As an emerging technology, PROTAC greatly expands the possibility of target selection
for human drug development in the future. We also look forward to the progress of science
and the development of technology, protein degradation therapy can achieve more
breakthrough achievements, and benefit the patients as soon as possible!

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6338-55-2) for PROTAC development.

Reference:
[1] Garber, K. The PROTAC gold rush. Nat Biotechnol (2021).
Related articles:
[1] PROTACs VS. Tranditional Small Molecule Inhibitors
[2] Focus On PROTAC: Summary Of Targets From 2001 To 2019
[3] Peptide PROTAC in Drug Development
[4] PROTACs and Targeted Protein Degradation